The pathogenesis of schizophrenia at least partially attributes to genetic variants. Given the widely accepted "dopamine hypothesis" for schizophrenia, polymorphism of Ser311Cys in the dopamine receptor-2 (DRD2) gene should be an important subject for further studies. In this application, we propose to generate DRD2 Ser311Cys knock-in mice, where the schizophrenia- associated single nucleotide polymorphism replaces the corresponding nucleotide in the genome of the mouse. Moreover, this novel mutant mouse model is featured by (1) the use of C57/BL6 ES cells in order to have an isogenic background between knock-in and wild-type mice and (2) the deletion of PGK-neo selection marker with the Cre/loxP recombination system in order to minimize the potential effect of genomic alterations that are produced by recombination procedures on DRD2 expression. With these knock-in mice, we will determine DRD2 expression, DRD2 receptor function, dopamine metabolism, and the potential morphological changes in certain selected brain regions. Furthermore, the use of a behavioral test battery that measures aggressive behaviors, locomotion, pre-pulse inhibition, nesting/reproductive performance, "despair" behaviors, social interaction, and working memory represents a comprehensively screening paradigm for the possible behavioral phenotypes pertinent to mental illness that may be associated with the polymorphism. In order to determine whether the gene dosage plays a role in these molecular/neuronal/behavioral responses, both homozygous and heterozygous knock-in mice together with wild-type controls will be examined in all the planned experiments. Through these studies, we will document whether this polymorphism is or not of pathophysiological significance related to schizophrenia. Relevance to Public Health: These studies should provide a novel tool (knock-in mice) for the studies of DRD2 polymorphism in laboratories, and may also reveal how this polymorphism affects molecular/neuronal/behavioral functions that may significantly implicated in schizophrenia. Polymorphism of Ser311Cys in the dopamine receptor-2 (DRD2) gene is repeatedly reported to associate with schizophrenia, while it is not clear whether this polymorphism is of pathophysiological significance. Here we propose to generate DRD2 Ser311Cys knock-in mice and develop a comprehensive experimental plan to characterize these mutant mice at the molecular, receptor functional, neuronal, morphological and behavioral levels. The results from these studies are able to provide a valuable mouse model as well as evidence on whether or how this polymorphism is involved in the pathogenesis of schizophrenia.